ed bio sorbonne paris cite - L`Institut de Formation Doctorale

ED BIO SORBONNE PARIS CITE Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : UMR1141, PROTECT (Promoting research oriented towards early CNS therapies)
Nom et prénom du Directeur : GRESSENS Pierre, MD, PhD
Téléphone : +331 40031976
Télécopie : +331 40031920
courriel : [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Developmental vulnerability, innovative assessment, and neuroprotection of
the immature brain
Nom et prénom du responsable : BAUD Olivier, MD, PhD
Qualité du responsable : PU-PH
Téléphone : +331 40034109
Télécopie : +331 40032470
courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : VODJDANI Guilan, PhD
Qualité : DR2-CNRS
Téléphone : +331 40031972
Télécopie : +331 40031920
courriel : [email protected]
Titre du sujet proposé :
Impact d’un déficit sérotoninergique maternel sur le développement du cerveau de la
descendance
Impact of a maternal serotonergic deficit on the progeny’s brain development
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lines maximum) :
This project deals with our interest on the maternal effect, by which the mother’s genotype and
physiological status modify normal fetal growth, and on neurotransmitters which may behave as trophic
factors in utero. Actually, in a mouse model we have developed, we will address the impact of the lack or
lowered-levels of maternal serotonin (5-HT) during gestation on progeny’s brain development and
function and on the setting of neurotransmitter systems.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Nom, prénom du directeur de l'unité de recherche : GRESSENS Pierre, MD, PhD
Numéro de l'unité de recherche (et établissement de rattachement) : UMR1141 Inserm/Paris Diderot
Nom, prénom du responsable de l'équipe d'accueil (EAD) : BAUD Olivier, MD, PhD
Nom, prénom du directeur de thèse : VODJDANI Guilan, PhD
Titre du sujet de thèse proposé : Impact of a maternal serotonergic deficit on the progeny’s brain
development
Citer 5 mots clés (key words) : Maternal effect ; serotonin ; brain development
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
Fetal and perinatal periods constitute a particularly sensitive time-window in the functional programming
of normal developing brain which may constitute a target that later leads to pathological conditions.
Early-life alterations and environmental changes can permanently influence the final brain setting and
function, and thus lead to neuropsychiatric diseases. In particular, the mother’s physiological status can
modify normal fetal growth. For instance, serotonin (5-HT) is known as a trophic factor of brain
development in utero before it acts as a neurotransmitter, and we have demonstrated the crucial role of
circulating maternal 5-HT on the fetus development (Côté et al, PNAS 2007).
The aim of the present project is to study the influence of the lack or lowered-levels of maternal 5-HT
during pregnancy on the progeny's brain structure and function during development. 5-HT is synthesized
by tryptophan hydroxylase (TPH) encoded by two genes, Tph1 and Tph2, the expression of Tph2 being
neuronal and that of Tph1 non-neuronal (Côté et al, PNAS 2003). Since Tph1 and Tph2 mRNAs are
detected from E15 and E11 respectively in the embryo, the 5-HT pool necessary early in embryogenesis
is not produced endogenously but of maternal origin. In a Tph1-KO mouse model we developed, we
have shown that a 95% decrease of blood 5-HT in the Tph1-/- mother during pregnancy impairs fetal
growth and heart development (Côté et al, PNAS 2007; Fligny et al, FASEB J 2008). Our first data on
the progeny’s fetal brain shows a 25 to 30% decrease in cell proliferation. Further, the existence of an
impact of maternal 5-HT on integrated functions is confirmed by our recent finding of altered behaviors
and sleep regulation in wild-type (wt) adult offspring born to 50%- (Tph1+/-) or 5%- (Tph1-/-) 5-HTdeficient mothers as compared to those born to wt (Tph1+/+) mothers (Jaliffa et al., in preparation). In
depth exploration of the influence of low maternal 5-HT levels on brain development and of its long term
consequences thus remains an important issue.
This proposal relies on animal models, available in our laboratory, which will be studied at prenatal and
postnatal stages. Brain anatomy and molecular status will be compared between wt progeny from wt
mothers and from Tph1+/- mothers that bear half the level of normal circulating 5-HT. The screening of
brain regions will be performed to pick out the prominent modified structures and the brain cytoarchitecture will be investigated. The expression profile of the serotonergic components, such as TPH2,
5-HT receptors or its transporter SERT, and those of other neurotransmitter systems will be determined.
Neurogenesis at different embryonic stages will also be investigated. The following exploratory
approaches will be used: biochemical and molecular measurements (HPLC, RT-qPCR, and protein
detection), histology, immunohistochemistry, in situ hybridization, microscopy.
The issues that will be tackled in this project should give us a comprehensive overview not only on how
neurodevelopment is disarrayed in the absence of maternal 5-HT contribution during fetal life, but should
also emphasize on serotonin as an environmental factor which participates in shaping the prodigy’s brain
and which can permanently influence it’s final structure and affect the offspring’s behavior.
Indiquez les cinq meilleures publications récentes de l’équipe :
- Sigoillot, S. M., Iyer, K., Binda, F., Gonzalez-Calvo, I., Talleur, M., Vodjdani, G., Isope, P. and Selimi, F. The
secreted protein C1QL1 and its receptor, the adhesion-GPCR BAI3, control the synaptic connectivity of excitatory
inputs converging on cerebellar Purkinje cells. Cell Reports, 2015, 10, 1-13.
- Bouaziz, E., Emerit, M. B., Vodjdani, G., Gautheron, V., Hamon, M., Darmon, M. and Masson, J. Neuronal
phenotype dependency of agonist-induced internalization of the 5-HT1A serotonin receptor. J Neurosci, 2014, 34,
282-294.
- Avci, H. X., Lebrun, C., Wehrlé, R., Doulazmi, M., Masatsugu, E., Vodjdani, G., Sotelo, C., Flamant, F. and
Dusart, I. Thyroid hormone triggers the developmental loss of axonal regenerative capacity via TRα1 and Klf9 in
Purkinje cells. Proc. Natl. Acad. Sci. USA, 2012, 109, 14206-14211.
- Fligny C, Fromes Y, Bonnin P, Darmon M, Bayard E, Launay J-M, Côté F, Mallet J, Vodjdani G. Maternal
serotonin influences cardiac function in adult offspring. FASEB J, 2008, 22: 2340-49.
- Côté F, Fligny C, Bayard E, Launay J-M, Gershon M D, Mallet J, Vodjdani G. Maternal serotonin is essential for
embryonic development. Proc Natl Acad Sci USA, 2007; 104: 329-34.